Connective Tissue Disorder Inherited Disorder

name	description	evidence	review_notes
Classical EDS (cEDS)	Characterized by skin hyperextensibility, atrophic scarring, and joint hypermobility.	TRUNCATED	None
Hypermobile EDS (hEDS)	Characterized by generalized joint hypermobility, often with recurrent joint dislocations and chronic pain.	TRUNCATED	None
Vascular EDS (vEDS)	Most severe form, characterized by thin, translucent skin, arterial, intestinal, and uterine fragility.	TRUNCATED	None
Kyphoscoliotic EDS (kEDS)	Characterized by kyphoscoliosis, hypotonia, and ocular fragility	TRUNCATED	Added an additional clinically relevant subtype.

0

population

Global

percentage

0.02

evidence

reference	supports	snippet	explanation
PMID:28077691	PARTIAL	The cohort held 1427 unique persons with Ehlers-Danlos Syndrome, giving a national prevalence of 0.02%.	The study confirms a prevalence of 0.02%, but this data is specific to the Danish population. The statement claims this prevalence on a global scale, which the provided literature does not support.

0

phase

Onset

age_range

Birth-40

evidence

reference	supports	snippet	explanation
PMID:32333004	NO_EVIDENCE	Systemic sclerosis is a heterogeneous, multisystem disease. It can occur at any age, but most patients develop the disease between the age of 40 to 50 years.	This study is about systemic sclerosis and does not provide evidence regarding the progression or onset of Ehlers-Danlos Syndrome specifically.
PMID:21193204	SUPPORT	Patients whose first echocardiogram was obtained in late childhood or adulthood were less likely to have aortic dilation (P < .002) than those whose first echocardiogram was obtained in early childhood.	This study suggests that certain clinical findings related to EDS, such as aortic dilation, are more pronounced in childhood, supporting earlier onset and progression.
PMID:24499752	SUPPORT	There is a much greater prevalence of obstetric and gynecologic issues reported by women with Ehlers-Danlos syndrome than in the general population. Additionally, rates differed significantly among the three most common types of Ehlers-Danlos syndrome with vascular type having the highest rates of adverse pregnancy outcomes and menstrual abnormalities.	The study discusses the prevalence of gynecologic and obstetric issues in women with Ehlers-Danlos Syndrome, implying that some symptoms and complications start or can be observed from an early age.
PMID:29982180	SUPPORT	Arterial fragility is an important characteristic of kyphoscoliotic EDS. It manifests as spontaneous arterial rupture, dissections and dissecting aneurysms which may occur even during early childhood.	This study highlights that arterial fragility in kyphoscoliotic EDS can manifest as early as childhood, supporting the statement regarding early onset and progression of the disease.

1

phase

Peak Symptoms Development

age_range

10-30

evidence

reference	supports	snippet	explanation
PMID:37261967	REFUTE	OBJECTIVE: This review sought to identify studies regarding aging in hEDS/HSD... No study had a stated aim regarding aging in hEDS/HSD, but all studies corroborated earlier natural history studies describing the age-related trajectory of manifestations in younger people. Studies found that symptom progression was heterogeneous, multisystemic, and unpredictable.	The statement that there is a common age range where symptoms peak is refuted by the literature's indication that symptom progression is heterogeneous, multisystemic, and unpredictable.

review_notes

Added an additional phase to describe the common age range where symptoms peak.

0

name

Collagen Abnormalities

description

Mutations in genes encoding collagen or collagen-modifying enzymes lead to defective collagen synthesis and assembly.

evidence

reference	supports	snippet	explanation
PMID:7086195	SUPPORT	Several abnormalities in collagen biosynthesis have been described in patients with Ehlers-Danlos syndrome. Examples of collagen structural mutations as well as post-translational enzymatic defects have been detected.	This reference confirms that mutations affecting collagen synthesis and enzymes responsible for collagen modification are associated with Ehlers-Danlos Syndrome.
PMID:37187299	SUPPORT	Vascular Ehlers-Danlos Syndrome (vEDS) is a rare autosomal dominant disease caused by mutations in the COL3A1 gene.	This reference identifies specific gene mutations (e.g., COL3A1) responsible for defective collagen synthesis leading to Ehlers-Danlos Syndrome.
PMID:2010058	SUPPORT	Recently, several mutations in three other collagen genes (COL2A1, COL3A1, and COL4A5) have been found in probands with genetic diseases involving tissues rich in these collagens.	The reference supports the statement by elaborating on how mutations in various collagen genes lead to defects tied to diseases including Ehlers-Danlos Syndrome.
PMID:30246406	SUPPORT	Human EDS may be caused by variants in several different genes including COL5A1, which encodes the collagen type V alpha 1 chain.	This reference describes how mutations in the COL5A1 gene can result in defective collagen synthesis, aligned with the nature of Ehlers-Danlos Syndrome.
PMID:30668708	SUPPORT	Bi-allelic loss-of-function mutations in the adipocyte enhancer-binding protein 1 (AEBP1) gene were reported in three families with an autosomal recessive EDS-like condition.	The reference confirms that mutations in genes involved in collagen biosynthesis or assembly can lead to EDS-like conditions.

1

name

Connective Tissue Fragility

description

Abnormal collagen leads to weakened connective tissues throughout the body.

evidence

reference	supports	snippet	explanation
PMID:358109	SUPPORT	The cardinal features are cutaneous hyperextensibility, joint hypermobility, bleeding diathesis, and tissue fragility, and these features lead to a large variety of additional manifestations.	The provided snippet mentions tissue fragility as a cardinal feature of Ehlers-Danlos Syndrome (EDS), which is consistent with the statement that abnormal collagen leads to weakened connective tissues.
PMID:36960056	SUPPORT	pEDS is caused by heterozygous missense mutations in C1R and C1S genes of the classical complement C1 complex.	This reference explains that pEDS is related to these genetic mutations which interfere with the collagen matrix, fitting the description of abnormal collagen leading to connective tissue fragility.
PMID:1448	SUPPORT	Any defect in the normal mechanisms responsible for the synthesis and secretion of collagen molecules or the deposition of these molecules into extracellular fibers could result in abnormal fibrillogenesis; such defects could result in a connective tissue disease.	This reference discusses how defects in collagen mechanisms can lead to connective tissue diseases, supporting the statement about abnormal collagen leading to connective tissue fragility.
PMID:31329366	SUPPORT	Collagen, which forms the framework of vessel walls, is altered in many patients with Ehlers-Danlos syndrome (EDS) leading to weakening of the vessel wall or the supporting tissues.	This reference directly supports the statement by mentioning how altered collagen in EDS patients leads to weakening of vessel walls and supporting tissues.

2

name

Tissue Injury and Dysfunction

description

Fragile tissues are prone to damage, leading to manifestations like joint dislocations, organ ruptures, and poor wound healing.

evidence

reference	supports	snippet	explanation
PMID:24443025	PARTIAL	The Ehlers-Danlos Syndromes comprise a heterogeneous group of diseases, which are characterized by fragility of the soft connective tissues and widespread manifestations in skin, ligaments and joints, blood vessels and internal organs... The clinical spectrum varies from mild skin and joint hyperlaxity to severe physical disability and life-threatening vascular complications.	The excerpt confirms tissue fragility and various manifestations affecting skin, joints, and internal organs, but does not explicitly mention every detail cited in the statement such as joint dislocations, organ ruptures, or poor wound healing.
PMID:29982180	PARTIAL	Arterial fragility is an important feature of the disease... Arterial fragility is an important characteristic of kyphoscoliotic EDS. It manifests as spontaneous arterial rupture, dissections and dissecting aneurysms.	The excerpt supports the statement by highlighting arterial fragility and spontaneous ruptures, contributing to tissue injury and dysfunction. However, it does not explicitly mention joint dislocations or poor wound healing.
PMID:19592142	PARTIAL	Easy bruising and bleeding are prominent features of some heritable disorders of connective tissue (HDCT), resulting from fragility of capillaries and the perivascular connective tissue... In the vascular subtype of EDS, caused by defects in type III collagen, fragility of vessel walls can lead to life-threatening bleeding and premature death.	The text discusses tissue fragility leading to bruising and bleeding, supporting aspects of tissue injury and dysfunction. However, it does not explicitly address joint dislocations or organ ruptures.

0

category

Musculoskeletal

name

Joint Hypermobility

frequency

VERY_FREQUENT

diagnostic

True

sequelae

Recurrent Joint Dislocations Chronic Joint Pain

evidence

reference	supports	snippet	explanation
PMID:34807421	SUPPORT	Currently, musculoskeletal manifestations related to joint hypermobility are perceived as the most prevalent determinants of the quality of life of affected individuals.	This reference confirms that musculoskeletal manifestations, including joint hypermobility, are highly prevalent in individuals with Ehlers-Danlos Syndrome (EDS).
PMID:29915965	SUPPORT	Increasing data demonstrate that pain is a major disability determinator in JH and EDS. Recent findings confirm a complex pathogenesis for pain in JH and EDS and suggest a potential role for joint instability, central sensitization and small fiber neuropathy.	This reference supports the statement by highlighting the high frequency and significant impact of joint hypermobility (JH) and associated chronic joint pain and instabilities in EDS.
PMID:31562935	SUPPORT	Pain is one of the most common symptoms reported in individuals with Ehlers-Danlos syndromes.	This reference supports the statement by highlighting that chronic joint pain is a frequent issue in those with EDS, reinforcing the high prevalence of musculoskeletal symptoms including joint hypermobility.
PMID:37726791	SUPPORT	The Ehlers-Danlos syndromes are a group of clinically and genetically heterogeneous hereditary diseases affecting the connective tissue. They are characterized by hypermobility of the joints, hyperextensible skin and friable tissue.	This reference supports the statement by acknowledging hypermobility of the joints as a characteristic of EDS, along with chronic pain and other musculoskeletal features.

1

category

Dermatologic

name

Skin Hyperextensibility

frequency

VERY_FREQUENT

evidence

reference	supports	snippet	explanation
PMID:358109	SUPPORT	The cardinal features are cutaneous hyperextensibility, joint hypermobility, bleeding diathesis, and tissue fragility...	The reference clearly states that cutaneous (skin) hyperextensibility is one of the cardinal features of Ehlers-Danlos Syndrome (EDS). This aligns with the statement indicating a high frequency dermatologic phenotype of skin hyperextensibility in EDS.
PMID:30837697	SUPPORT	All individuals with these atypical variants exhibited skin hyperextensibility as seen in individuals with classical EDS and classical-like EDS...	The reference shows that skin hyperextensibility is a consistent clinical feature across different EDS subtypes, which supports the statement about its high prevalence as a dermatologic phenotype.
PMID:434850	SUPPORT	Hyperextensibility of the skin in this region developed within the subsequent five years...	Although this case was localized, it still confirms the presence of skin hyperextensibility in a patient with EDS, reinforcing its association with EDS.
PMID:31904772	SUPPORT	Of the 13 subtypes of Ehlers-Danlos Syndromes (EDSs)...the authors provide an overview of hEDS symptoms and... current treatment options.	The overview and symptoms of various EDS subtypes include skin manifestations such as hyperextensibility, supporting the statement about its high prevalence.
PMID:6733946	SUPPORT	Collagen fibrils showed a distorted arrangement... abnormal collagen fibrils in normal skin suggests one of eight types of Ehlers-Danlos syndrome.	This reference details abnormal collagen fibrils and associates them with EDS, indicating that skin hyperextensibility is a frequent manifestation.

2

category

Dermatologic

name

Poor Wound Healing

frequency

FREQUENT

evidence

reference	supports	snippet	explanation
PMID:19055167	SUPPORT	Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders characterized by hyperextensibility, delayed wound healing, joint hypermobility, thin skin, easy bruising, tissue fragility, 'cigarette-paper' scarring over bony prominences, mitral valve prolapse, and other findings.	This reference directly mentions delayed wound healing as a characteristic of Ehlers-Danlos syndrome.
PMID:2728341	SUPPORT	Although delayed wound healing has been reported to be a complication of Ehlers-Danlos syndrome in humans, using clinical and histologic criteria, wound healing in dogs and cats with Ehlers-Danlos syndrome appears to be similar to nonaffected animals.	This reference acknowledges delayed wound healing in humans with Ehlers-Danlos syndrome, although the study was conducted on animals.
PMID:20847697	SUPPORT	Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy bruising, and generalized joint hypermobility.	This reference lists delayed wound healing as a characteristic feature of classic Ehlers-Danlos syndrome.

3

category

Cardiovascular

name

Arterial Dissection and Rupture

frequency

VERY_FREQUENT

evidence

reference	supports	snippet	explanation
PMID:19462862	SUPPORT	The mutation of the COL3A1 gene which encodes type III collagen, is responsible for early vascular (spontaneous arterial rupture or dissection) ...	The literature specifies that the COL3A1 mutation, causing vascular EDS, leads to early vascular events including spontaneous arterial rupture or dissection.
PMID:30999998	SUPPORT	The only published clinical trial to date demonstrated the benefit of celiprolol on arterial morbimortality.	The literature states that vascular EDS results in exceptional arterial fragility, justifying a high frequency of arterial dissection and rupture.

subtype

Vascular EDS

4

category

Ophthalmologic

name

Keratoconus

frequency

OCCASIONAL

evidence

reference	supports	snippet	explanation
PMID:36237549	SUPPORT	In addition to these commonly recognized phenotypes, recent studies have notably highlighted variable ophthalmic features in EDS.	The literature highlights that Ehlers-Danlos syndrome has variable ophthalmic features, which supports the assertion that ophthalmologic phenotypes, including keratoconus, are part of the syndrome.
PMID:28757364	NO_EVIDENCE	As the two patients reported here illustrate, patients with kEDS-PLOD1 do not always have a kyphoscoliosis present at birth or in the first year of life, neither do they necessarily develop kyphoscoliosis later in infancy.	This reference talks mainly about kyphoscoliotic EDS and its genetic underpinnings, without specifically mentioning ophthalmologic features or keratoconus.
PMID:9493273	NO_EVIDENCE	Keratoconus is most commonly an isolated disorder, although several reports describe an association with Down syndrome, Leber's congenital amaurosis, and mitral valve prolapse.	This reference discusses keratoconus but does not specifically link it to Ehlers-Danlos syndrome.
PMID:14679583	SUPPORT	The brittle cornea syndrome (BCS) is a generalized connective tissue disorder characterized by corneal rupture following only minor trauma, keratoconus or keratoglobus, blue sclerae, hyperelasticity of the skin without excessive fragility, and hypermobility of the joints.	The brittle cornea syndrome listed here shares ophthalmologic phenotypes, including keratoconus, similar to Ehlers-Danlos syndrome.
PMID:37074408	NO_EVIDENCE	OI patients had tomographically suspect corneas when using keratoconus diagnostic indices.	This reference discusses keratoconus in the context of osteogenesis imperfecta, not Ehlers-Danlos syndrome.

review_notes

Added less common phenotype for better completeness.

name	presence	evidence	subtype
Collagen Type III	Decreased or Abnormal	TRUNCATED	Vascular EDS
Collagen Type V	Decreased or Abnormal	TRUNCATED	Classical EDS

0

name

COL1A1

evidence

reference	supports	snippet	explanation
PMID:36896471	SUPPORT	Pathogenic variants in COL1A1 and COL1A2 are involved in osteogenesis imperfecta (OI) and, rarely, Ehlers-Danlos syndrome (EDS) subtypes and OI-EDS overlap syndromes (OIEDS1 and OIEDS2, respectively).	This statement supports that pathogenic variants in COL1A1 are associated with some subtypes of Ehlers-Danlos Syndrome (EDS).

association

Pathogenic Variants

1

name

COL3A1

evidence

reference	supports	snippet	explanation
PMID:34560710	SUPPORT	vEDS patients are at risk of blood vessel rupture due to possession of pathogenic variants of the COL3A1 gene, which encodes type III collagen.	The literature explicitly states that vascular Ehlers-Danlos syndrome (vEDS) is caused by pathogenic variants in the COL3A1 gene.
PMID:30837697	SUPPORT	Vascular EDS (vEDS) is caused by pathogenic variants in COL3A1, most frequently glycine substitutions.	The abstract confirms the association of vascular EDS with pathogenic variants in the COL3A1 gene.
PMID:35699227	SUPPORT	Carriers of pathogenic or likely pathogenic COL3A1 variants were retrospectively identified through registries and specialized clinics.	The study supports the association between pathogenic COL3A1 variants and vascular Ehlers-Danlos syndrome.

association

Pathogenic Variants

subtype

Vascular EDS

2

name

COL5A1

evidence

reference	supports	snippet	explanation
PMID:16278879	SUPPORT	Mutations in the COL5A1 and the COL5A2 gene, encoding the alpha1 and the alpha2-chain of type V collagen respectively, are identified in approximately 50% of patients with a clinical diagnosis of classic EDS.	The reference clearly states that mutations in the COL5A1 gene are associated with classical Ehlers-Danlos Syndrome, thus supporting the statement.

association

Pathogenic Variants

subtype

Classical EDS

3

name

PLOD1

evidence

reference	supports	snippet	explanation
PMID:32174067	SUPPORT	Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive connective tissue disorder... The disorder results from a deficiency of the enzyme collagen lysyl hydroxylase 1 due to mutations in the gene PLOD1.	This source clearly states that pathogenic variants in the PLOD1 gene are responsible for kyphoscoliotic Ehlers-Danlos syndrome.
PMID:15979919	SUPPORT	The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) is an inheritable connective tissue disorder characterized by a deficiency of lysyl hydroxylase due to mutations in PLOD1.	This reference supports the association between PLOD1 mutations and kyphoscoliotic Ehlers-Danlos syndrome.
PMID:29982180	SUPPORT	Pathogenic variants in the lysyl-hydroxylase-1 gene (PLOD1) are responsible for the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS).	This source reinforces the role of PLOD1 pathogenic variants in causing kyphoscoliotic Ehlers-Danlos syndrome.
PMID:36054293	SUPPORT	The autosomal recessive kyphoscoliotic EDS results from deficiency of either lysyl hydroxylase 1 (encoded by PLOD1), crucial for collagen cross-linking...	This study adds further confirmation of the genetic association between PLOD1 and kyphoscoliotic Ehlers-Danlos syndrome.

association

Pathogenic Variants

review_notes

Added an additional gene (PLOD1) known to be associated with Kyphoscoliotic EDS as an example of a less common subtype.

subtype

Kyphoscoliotic EDS

0

name

Physical Trauma

evidence

reference	supports	snippet	explanation
PMID:26452443	SUPPORT	Ehlers-Danlos syndrome remains undetected until the patient, usually in the pediatric age, shows extensive or severe mucocutaneous injuries after only minor traumas.	The snippet indicates that minor physical trauma can exacerbate symptoms by causing severe mucocutaneous injuries in EDS patients.
PMID:28186390	SUPPORT	Pain, which is often one of the first symptoms to occur, may be widespread or localized to one region such as an arm or a leg. The causes of pain in this condition are multifactorial and include joint subluxations and dislocations...	The excerpt mentions joint subluxations and dislocations as causes of pain in EDS, which can be exacerbated by physical trauma.
PMID:23095510	SUPPORT	Optimal therapy for these patients includes the awareness that EDS is a systemic disease involving fragility, bleeding and spontaneous perforations from almost all organ systems.	This highlights the fragility associated with EDS, indicating that physical trauma can exacerbate symptoms by causing bleeding and perforations.

effect

Exacerbates Symptoms

1

name

Repetitive Motion

evidence

reference	supports	snippet	explanation
PMID:31582002	SUPPORT	Symptomatic joint hypermobility can result from soft tissue injury or muscular strain caused by muscular imbalance.	The text from the literature indicates that repetitive use injury can result from symptomatic joint hypermobility, which is consistent with the statement that repetitive motion exacerbates symptoms.
PMID:32175940	PARTIAL	Thirteen EDS subtypes are recognized, with a wide degree of symptom overlap among subtypes and with other connective tissue disorders.	Although it discusses the overlap of symptoms, it does not directly state that repetitive motion exacerbates these symptoms. However, it implies increased fragility and susceptibility, which could be worsened by repetitive motion.

effect

Exacerbates Symptoms

review_notes

Added based on domain knowledge as repetitive motion is often a factor in exacerbating symptoms for connective tissue disorders.

0

name

Supportive Care

description

Management of pain, physical therapy to strengthen joints, and prevention of complications.

evidence

reference	supports	snippet	explanation
PMID:38189943	SUPPORT	Affected patients require multimodal pain management considering their individual needs, disease-specific features, and comorbidities.	This reference highlights the need for multimodal pain management in Ehlers-Danlos syndrome (EDS) patients, which is a component of supportive care.
PMID:34145717	SUPPORT	Physiotherapy benefits on proprioception and pain in patients with hEDS even if robust randomized control studies are missing.	This reference supports the use of physical therapy, which strengthens joints and manages pain, aligning with the statement.
PMID:17067502	SUPPORT	Preparticipation cardiothoracic and orthopedic screening is highly recommended for athletes with EDS, and appropriate cardiovascular, orthopedic, gastrointestinal, neurologic, and dermatologic management can often allow patients with EDS to remain active.	This reference supports the prevention of complications through preparticipation screening and various management practices, which falls under supportive care.
PMID:32941194	SUPPORT	The creation of multidisciplinary care teams and tertiary referral centers is helping improve outcomes.	This reference highlights the importance of multidisciplinary care, essential in the supportive management of EDS.

1

name

Surgical Interventions

description

May be needed for severe joint instability or life-threatening complications like arterial dissections.

evidence

reference	supports	snippet	explanation
PMID:32904109	SUPPORT	Patients with joint hypermobility syndrome (JHS) might also present with similar symptomatology. This article will focus on the surgical management of patients with knee or shoulder abnormalities related to hEDS/JHS.	This article supports the need for surgical interventions for severe joint instability in patients with hypermobile Ehlers-Danlos Syndrome, which can be considered analogous to severe cases in other types of EDS.
PMID:30999998	SUPPORT	The only published clinical trial to date demonstrated the benefit of celiprolol on arterial morbimortality... During the period surveyed, the authors observed a statistically significant difference in the ratio of hospitalizations for acute arterial events/hospitalizations for regular follow-up before and after 2011.	While the article mainly discusses the use of celiprolol, it acknowledges arterial events and their impact, implicitly supporting the need for interventions, which may include surgical options, in severe cases involving life-threatening arterial complications.
PMID:33650410	SUPPORT	The vascular subtype of EDS (type IV) is defined by characteristic facial features, translucent skin, easy bruising, and spontaneous arterial rupture and visceral perforation of such organs as the uterus and intestines, with possible life-threatening consequences.	This reference supports the need for surgical interventions in life-threatening complications like spontaneous arterial rupture and visceral perforation in vascular EDS.

2

name

Lifestyle Modifications

description

Avoiding high-impact activities and contact sports to prevent injury.

evidence

reference	supports	snippet	explanation
PMID:17067502	SUPPORT	Preparticipation cardiothoracic and orthopedic screening is highly recommended for athletes with EDS, and appropriate cardiovascular, orthopedic, gastrointestinal, neurologic, and dermatologic management can often allow patients with EDS to remain active.	The literature suggests avoiding high-impact activities and specific management strategies, which supports the statement.
PMID:35756986	SUPPORT	The results suggest that exercise and rehabilitation may be beneficial for various physical and psychological outcomes.	While exercise and rehabilitation are recommended, the literature implies careful selection of physical activities to prevent injury, indirectly supporting the avoidance of high-impact activities and contact sports.

3

name

Orthotic Interventions

description

Use of orthotic devices to support unstable joints.

evidence

reference	supports	snippet	explanation
PMID:27349123	SUPPORT	ignorance of effective treatments such as oxygen therapy and orthotics are new concepts that should shake the prejudices derived from the history of this disease.	This reference mentions orthotic devices as part of the effective treatments for Ehlers-Danlos syndrome.
PMID:32709178	SUPPORT	Occupational therapy and bracing were the most effective options with 70% of patients reporting improvement.	This reference supports the use of orthotic devices (e.g., bracing) as effective in the management of EDS.

review_notes

Added orthotic interventions commonly recommended in the management of EDS.

species	genotype	genes	associated_phenotypes
Mouse	Col5a1 knockout	Col5a1	Skin hyperextensibility Joint hypermobility
Mouse	Col3a1 heterozygous	Col3a1	Vascular fragility Arterial rupture